Interleukin-1 in the Pathogenesis and Treatment of Inflammatory Diseases

From www.bloodjournal.org by guest on September 2, 2017. For personal use only. Review article Interleukin-1 in the pathogenesis and treatment of inflammatory diseases Charles A. Dinarello1,2 1Department of Medicine, University of Colorado, Aurora, CO; and 2Department of Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands More than any other cytokine family, the family, IL-1␤ has emerged as a therapeu- eases such as gout, type 2 diabetes, heart IL-1 family of ligands and receptors is tic target for an expanding number of failure, recurrent pericarditis, rheumatoid primarily associated with acute and systemic and local inflammatory condi- arthritis, and smoldering myeloma also chronic inflammation. The cytosolic seg- tions called autoinflammatory diseases. are responsive to IL-1␤ neutralization. ment of each IL-1 receptor family member For these, neutralization of IL-1␤ results This review summarizes acute and contains the Toll-IL-1-receptor domain. in a rapid and sustained reduction in chronic inflammatory diseases that are This domain is also present in each Toll- disease severity. Treatment for autoim- treated by reducing IL-1␤ activity and like receptor, the receptors that respond mune diseases often includes immuno- proposes that disease severity is affected to microbial products and viruses. Since suppressive drugs whereas neutraliza- by the anti-inflammatory members of the Toll-IL-1-receptor domains are functional tion of IL-1␤ is mostly anti-inflammatory. IL-1 family of ligands and receptors. for both receptor families, responses to Although some autoinflammatory dis- (Blood. 2011;117(14):3720-3732) the IL-1 family are fundamental to innate eases are due to gain-of-function muta- immunity. Of the 11 members of the IL-1 tions for caspase-1 activity, common dis- Introduction Since the 1996 publication in Blood of “Biologic Basis for IL-1 activity. Blocking IL-1, particularly IL-1␤, is now the Interleukin-1 in Disease,”1 there have been several major advances standard of therapy for a class of inflammatory syndromes termed in understanding a role for IL-1 in the pathogenesis of disease. “autoinflammatory” diseases (reviewed by Simon and van der Because of its property as a hematopoietic factor, IL-1 was Meer5 and Masters et al6). Autoinflammatory syndromes are administered to patients to improve recovery after BM transplanta- distinct from autoimmune diseases. In autoimmune diseases, the tion (human responses to IL-1 were reviewed in detail in 1996).1 T cell is associated with pathogenesis as the dysfunctional cell or Effective in reducing the duration of thrombocytopenia and “driver” of inflammation. Immunosuppressive therapies targeting leukopenia, recipients of IL-1 therapy experienced unacceptable T-cell function as well as antibodies that deplete T and B cells are signs and symptoms of systemic inflammation, including hypoten- effective in treating autoimmune diseases. In contrast, in auto- sion. Therefore, attention was initially focused on blocking IL-1 inflammatory diseases, the monocyte-macrophage is the dysfunc- activity in sepsis with the use of the naturally occurring IL-1 tional cell, which directly promotes inflammation. Autoinflamma- receptor antagonist (IL-1Ra), now known by its generic name tory conditions are characterized by recurrent bouts of fever with anakinra. There were 3 controlled trials of anakinra in human sepsis. debilitating local and systemic inflammation; they are often Although in each trial there was a reduction in 28-day all-causes responsive to IL-1␤ blockade (Table 1). In general, these diseases mortality compared with placebo-treated patients, the reductions did not are poorly controlled with immunosuppressive therapies, and reach statistical significance.2 The failure of blocking IL-1 to signifi- responses to blocking TNF␣, if any, are modest. In this review, a cantly reduce mortality in septic shock is not unusual, because most growing number of unrelated diseases often responsive to blocking ␤ anticytokines and anti-inflammatory agents have also failed in sepsis IL-1 are discussed. trials (reviewed in Eichacker et al3). Subsequently, attention focused on blocking IL-1 in noninfec- tious, chronic inflammatory conditions, such as rheumatoid arthri- ␣ ␤ tis. Anakinra is approved for reducing the signs and symptoms of From IL-1 and IL-1 to the IL-1 superfamily rheumatoid arthritis and slows the progressive joint destructive of ligands and receptors characteristics of the disease. Anakinra has also been administered Similarities in the IL-1 family to patients with smoldering/indolent myeloma at high risk of progression to multiple myeloma. In combination with a weekly Although the original IL-1 family comprised only IL-1␣ and low dose of dexamethasone, anakinra treatment provided a signifi- IL-1␤, the IL-1 family has expanded considerably. As shown in cant increase in the number of years of progression-free disease.4 Table 2, there are 11 members. The IL-1R family has also expanded Consistently, there are no organ toxicities or gastrointestinal to 9 distinct genes and includes coreceptors, decoy receptors, disturbances with anakinra or other parenteral therapies to reduce binding proteins, and inhibitory receptors.7 In terms of human Submitted July 12, 2010; accepted January 18, 2011. Prepublished online as © 2011 by The American Society of Hematology Blood First Edition paper, February 8, 2011; DOI 10.1182/blood-2010-07-273417. The online version of this article contains a data supplement. 3720 BLOOD, 7 APRIL 2011 ⅐ VOLUME 117, NUMBER 14 From www.bloodjournal.org by guest on September 2, 2017. For personal use only. BLOOD, 7 APRIL 2011 ⅐ VOLUME 117, NUMBER 14 IL-1 IN INFLAMMATORY DISEASES 3721 Table 1. Blocking IL-1␤ in treatment of acute and chronic signal is initiated (Figure 1; Table 2). Family members IL-36␣, ␤, inflammatory diseases and ␥ (formerly termed IL-1F6, IL-1F8, and IL-1F9) bind to the Classic autoinflammatory diseases IL-1Rp2, recruit the same IL-1RAcP, and a proinflammatory signal Familial Mediterranean fever (FMF) is initiated. IL-36Ra (formerly IL-1F5) also binds to the IL-1Rp2, Pyogenic arthritis, pyoderma gangrenosum, acne (PAPA)*† but does not recruit IL-1RAcP and acts as the natural-occurring Cryopyrin-associated periodic syndromes (CAPS) receptor antagonist for IL-36␣, ␤, and ␥. IL-33 binds to ST2, also Hyper IgD syndrome (HIDS) recruits the IL-1RAcP, but Th2-like properties characterize IL-33. Adult and juvenile Still disease Schnitzler syndrome Thus, the 6 proinflammatory members of the IL-1 family each TNF receptor-associated periodic syndrome (TRAPS) recruit the IL-1RAcP coreceptor with the TIR domain and MyD88 Blau syndrome; Sweet syndrome docks to each. Deficiency in IL-1 receptor antagonist (DIRA) Active precursors Probable autoinflammatory diseases Recurrent idiopathic pericarditis With the sole exception of IL-1Ra, each member of the IL-1 family Macrophage activation syndrome (MAS) is first synthesized as a precursor without a clear signal peptide for Urticarial vasculitis ␣ Antisynthetase syndrome processing and secretion, and none are found in the Golgi. IL-1 Relapsing chondritis and IL-33 are similar in that their precursor forms can bind to their Behçet disease respective receptor and trigger signal transduction. Although Erdheim-Chester syndrome (histiocytosis) recombinant mature forms of IL-1␣ and IL-33 are active, it remains Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) unclear whether the mature forms are representative of the Common diseases mediated by IL-1␤ naturally occurring IL-1␣ and IL-33 produced in vivo. The Rheumatoid arthritis‡ importance of the biologic activity of the IL-1␣ precursor is Periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA) discussed below. The precursor forms of IL-18 and IL-1␤ do not Urate crystal arthritis (gout) bind their respective receptors, are not active, and require cleavage Type 2 diabetes by either intracellular caspase-1 or extracellular neutrophilic pro- Smoldering multiple myeloma Postmyocardial infarction heart failure teases (see below). Osteoarthritis Dual-function cytokines Complete list of citations is in supplemental References (available on the Blood Web site; see the Supplemental Materials link at the top of the online article). IL-1␣ and IL-33 are “dual-function” cytokines in that in addition to *Incomplete responses to IL-1␤ blockade have been reported. binding to their respective cell surface receptors, the intracellular †The combination of IL-1 plus TNF␣ have been used in some disorders. precursor forms translocate to the nucleus and influence transcrip- ‡Rheumatoid arthritis is also treatable with other anticytokines, antireceptors, 9,10 ␣ immunomodulating agents, and B cell–depleting antibodies. tion. IL-33 is a bona fide transcription factor, and the IL-1 N-terminal amino acids contain a nuclear localization site (re- 7 ␣ disease, the properties of IL-1 itself still remain the model for viewed in Dinarello ). In general, the nuclear function of IL-1 or mediating inflammation. As shown in Figure 1, IL-1␣ or IL-1␤ IL-33 is transcription of proinflammatory genes. For example, ␣ bind first to the ligand-binding chain, termed type I (IL-1RI). This expression of the N-terminal amino acids of IL-1 stimulates IL-8 is followed by recruitment of the coreceptor chain, termed the production in the presence of complete blockade of the IL-1RI on 10 accessory protein (IL-1RAcP). A complex is formed of IL-1RI plus the cell surface. IL-37, formerly IL-1F7, also translocates to the 11 IL-1 plus the coreceptor. The signal is initiated with recruitment of nucleus. but, in the case of IL-37, there is a net decrease in 11,12 the adaptor protein MyD88 to the Toll-IL-1 receptor (TIR) domain inflammation. As such, IL-37 is a unique ligand in the IL-1 (see “IL-1 and TLR share similar functions”). Several kinases are family because it functions as an anti-inflammatory cytokine phosphorylated, NF-␬B translocates to the nucleus, and the expres- (see below). sion of a large portfolio of inflammatory genes takes place.

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